The epidemic of type 2 diabetes (T2DM) that has affected the US and other populations in the last thirty years is a major public health problem. The most recent US estimates include a prevalence of more than 21 million and incidence of 1.6 million cases per year. The major human and economic costs associated with the epidemic are related primarily to the development of long-term complications that cause more cases of blindness, renal failure, and amputations than any other disease. T2DM also increases cardiovascular disease by 2-5 fold and is the leading cause of death and premature death in persons with diabetes. High quality clinical trials have established the importance of lowering glycemia with a variety of medications to reduce the long-term complications. One of the major challenges for practitioners is to choose, from the large armamentarium of glucose-lowering medications at their disposal, the optimal approach to achieve and then maintain good glycemic control for as long as possible. Evidence supporting the choice of one versus another agent as initial therapy or the choice of sequential versus combination therapy as an initial approach is clearly lacking. Comparative effectiveness research is a high priority to improve public health and maximize cost- effectiveness. Moreover, there are little data available to determine whether some therapies work better in individuals with particular characteristics compared to others;therefore, individualizing therapies to obtain maximum effectiveness remains in its infancy. We propose to address these questions in a randomized clinical trial in patients with recent onset (<3 years duration) T2DM that will compare the metabolic effects of five common glucose- lowering drugs when combined with metformin. Recruitment will be stratified to include patients who have been treated with metformin (n=5,500) for up to three years, and patients who are drug-naive (n=2,000). All will be randomly assigned to one of five drug regimens to be administered in combination with metformin. Subjects in the drug naive stratum will also be randomly assigned to be treated with the assigned drug as sequential therapy (ST) after glycemic control has deteriorated with metformin monotherapy, similar to traditional prescribing patterns, or to receive initial combination therapy (ICT). The one-half of the drug-naive stratum assigned to initial combination therapy will be included with the metformin-treated stratum in the analyses of the differences among the five drug combinations. The proposed partial factorial design is an efficient way to compare the five major diabetes drug combinations and examine two different treatment strategies in a single trial. The primary metabolic outcome will be time to failure defined as a HbA1c >7%, with area- under-the-curve HbA1c levels as a secondary metabolic outcome. Follow-up will be for a minimum of 4 (4-7) years. Determination and comparison of the other important attributes of the five combinations, including weight change, hypoglycemia, tolerability, effects on CVD risk factors, and cost will be performed. In addition, we will examine the phenotypic and, resources permitting, genotypic characteristics that are associated with metabolic response to and/or failure of the individual medication combinations and the two intervention strategies. The goal of the proposed U34 application is to complete the design and prepare for the implementation of a multicenter study to determine the most effective drug combinations and treatment strategies for T2DM that achieve and maintain the glycemic levels known to reduce long-term complications. Specifically, the U34 period will be used to: a) develop the protocol and manual of operations;b) recruit the clinical centers, laboratories, and reading and drug distribution centers;and c) establish recruitment strategies, identify patient populations and complete the IRB and other regulatory approval process to meet enrollment timelines. This preparation will ensure that the majority of clinical sites are ready to start randomizing patients as soon as possible after the study is funded, minimizing recruitment time and maximizing patient follow-up and power of the study. The results of this trial will identify the most effective means of treating glycemia in T2DM early in its course and will have major public health implications. PUBLIC HEALTH RELEVANCE: In order to avoid long-term complications that may affect people with type 2 diabetes, average blood sugar levels, as measured with the HbA1c assay, must be maintained in a near-normal range. Although there are many medications that are currently available to treat type 2 diabetes, we don't understand the most effective means of achieving and maintaining the target blood sugar levels over time. In addition, we don't know whether specific medications, or combinations of medications, are better for specific groups of people. The proposed study will compare two different strategies and five different medications for treating type 2 diabetes in order to determine how best to treat it. Since type 2 diabetes is now epidemic, affecting more than 20 million people in the US, comparing and selecting the most effective treatment methods will have a major public health impact.